GATA6 | Cancer Genetics Web

Paclitaxel

Prostate Cancer

Xicola RM, Manojlovic Z, Augustus GJ, et al.
Lack of APC somatic mutation is associated with early-onset colorectal cancer in African Americans.
Carcinogenesis. 2018; 39(11):1331-1341 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.

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FAT1

TET1

Zhu P, Wu J, Wang Y, et al.
LncGata6 maintains stemness of intestinal stem cells and promotes intestinal tumorigenesis.
Nat Cell Biol. 2018; 20(10):1134-1144 [PubMed] Related Publications

The intestinal epithelium harbours remarkable self-renewal capacity that is driven by Lgr5

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Cutaneous T-cell lymphoma

Kamijo H, Miyagaki T, Shishido-Takahashi N, et al.
Aberrant CD137 ligand expression induced by GATA6 overexpression promotes tumor progression in cutaneous T-cell lymphoma.
Blood. 2018; 132(18):1922-1935 [PubMed] Related Publications

CD137 and its ligand, CD137L, are expressed on activated T cells and antigen-presenting cells, respectively. Recent studies have shown that CD137L and CD137 are aberrantly expressed by tumor cells, especially in some hematopoietic malignancies, and interactions between these molecules on tumor cells promote tumor growth. In this study, we investigated the roles of CD137L and CD137 in cutaneous T-cell lymphoma (CTCL), represented by mycosis fungoides and Sézary syndrome. Flow cytometric analysis showed that primary Sézary cells and CTCL cell lines (Hut78, MyLa, HH, SeAx, and MJ) aberrantly expressed CD137L. CD137L expression by tumor cells in CTCL was also confirmed by immunohistochemistry. Anti-CD137L-neutralizing antibody inhibited proliferation, survival, CXCR4-mediated migration, and in vivo growth in CTCL cell lines through inhibition of phosphorylation of AKT, extracellular signal-regulated kinase 1/2, p38 MAPK, and JNK. Moreover, suppression of CD137L signaling decreased antiapoptotic proteins Bcl-2 and phosphorylated Bad. We also explored the transcription factor regulating CD137L expression. Because GATA6 has been proposed as an oncogene in many types of tumors with aberrant CD137L expression, we examined GATA6 expression and the involvement of GATA6 in CD137L expression in CTCL. DNA hypomethylation and histone acetylation induced GATA6 overexpression in CTCL cells. Furthermore, chromatin immunoprecipitation, luciferase reporter assay, and knockdown by short hairpin RNA showed that GATA6 directly upregulated CD137L expression. Inhibition of GATA6 resulted in decreased survival and in vivo growth in CTCL cells. Collectively, our findings prompt a novel therapeutic approach to CTCL based on the discovery that the GATA6/CD137L axis plays an important role in the tumorigenesis of CTCL.

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Skin Cancer

Liu Z, Dai J, Shen H
Systematic analysis reveals long noncoding RNAs regulating neighboring transcription factors in human cancers.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(9 Pt B):2785-2792 [PubMed] Related Publications

Long noncoding RNAs (lncRNAs) are proposed to play essential roles in regulating gene transcription. Moreover, a subset has been implicated in modulating the expression of the nearby loci. Here we systematically evaluated the relationship between lncRNAs and their neighboring genes based on transcriptome expression profiles from 4900 samples across 12 cancer types. Our findings reveal that lncRNAs, especially those of high syntenic conservation across species, are spatially correlated with transcription factors across the genome. Combining the methods of conservation, co-expression, and causal inference test, we identified a list of 28 lncRNA/TF regulatory pairs across 12 TCGA cancer types, and 19 of which were further confirmed in additional cancer cell lines. Several of these pairs, including PTV1/MYC and GATA6-AS1/GATA6, show prior evidence of regulatory relationships. Other candidates such as LINC00261/FOXA2 and PITRM1-AS1/KLF6 were novel. Our study highlights the significant roles of lncRNAs in tumorigenesis and provides a comprehensive overview of lncRNA regulation on its neighboring TF genes in human cancers.

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Cancer Prevention and Risk Reduction

Hsieh YY, Tung SY, Pan HY, et al.
Upregulation of bone morphogenetic protein 1 is associated with poor prognosis of late-stage gastric Cancer patients.
BMC Cancer. 2018; 18(1):508 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

BACKGROUND: Gastric cancer is the eighth most common cancer in Taiwan, with a 40% 5-year survival rate. Approximately 40% of patients are refractory to chemotherapy. Currently, the anti-HER2 therapy is the only clinically employed targeted therapy. However, only 7% patients in Taiwan are HER2-positive. Identifying candidate target genes will facilitate the development of adjuvant targeted therapy to increase the efficacy of gastric cancer treatment.
METHODS: Clinical specimens were analyzed by targeted RNA sequencing to assess the expression levels of target genes. Statistical significance of differential expression and correlation between specimens was evaluated. The correlation with patient survival was analyzed as well. In vitro cell mobility was determined using wound-healing and transwell mobility assays.
RESULTS: Expression of BMP1, COL1A1, STAT3, SOX2, FOXA2, and GATA6 was progressively dysregulated through the stages of gastric oncogenesis. The expression profile of these six genes forms an ubiquitously biomarker signature that is sufficient to differentiate cancer from non-cancerous specimens. High expression status of BMP1 correlates with poor long-term survival of late-stage patients. In vitro, suppression of BMP1 inhibits the mobility of the gastric cancer cell lines, indicating a role of BMP1 in metastasis.
CONCLUSIONS: BMP1 is upregulated in gastric cancer and is correlated with poor patient survival. Suppression of BMP1 reduced gastric cancer mobility in vitro. Our finding suggests that anti-BMP1 therapy will likely augment the efficacy of standard chemotherapy and improve the treatment outcome.

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Stomach Cancer

Gastric Cancer

Yunqi H, Fangrui Y, Yongyan Y, et al.
miR-455 Functions as a Tumor Suppressor Through Targeting GATA6 in Colorectal Cancer.
Oncol Res. 2019; 27(3):311-316 [PubMed] Related Publications

Emerging evidence indicates that microRNAs (miRNAs) are often aberrantly expressed in human cancers. Meanwhile, the importance of miRNAs in regulating multiple cellular biological processes has been appreciated. The aim of this study was to investigate the significance of miR-455 and identify its possible mechanism in regulating colorectal cancer (CRC) progression. We found that the expression of miR-455 was sharply reduced in CRC tissues and cell lines. Importantly, the low expression of miR-455 was associated with poor overall survival of CRC patients. Overexpression of miR-455 in CRC cell lines significantly inhibited cell proliferation and migration in vitro. Moreover, GATA-binding protein 6 (GATA6), whose expression can be inversely regulated by miR-455 in CRC cell lines, was validated as a direct target of miR-455. Overall, our results revealed that miR-455 functions as a tumor suppressor, and its downregulation may contribute to CRC progression. Our study may provide a novel therapeutic target for CRC in the future.

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Laryngeal Cancer - Molecular Biology

Zhao X, Zhang W, Ji W
miR-181a targets GATA6 to inhibit the progression of human laryngeal squamous cell carcinoma.
Future Oncol. 2018; 14(17):1741-1753 [PubMed] Related Publications

AIM: We sought to determine the function of miR-181a/GATA6 pathway in the progression of laryngeal squamous cell carcinoma (LSCC).
MATERIALS & METHODS: The expression of miR-181a and GATA6 were detected using quantitative real-time-PCR and western blotting in 127 LSCC samples and 32 corresponding control mucosa tissues. Cell death, migration and apoptosis were measured in Hep-2 cells using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), Transwell migration assay and apoptosis assay, respectively. The prognosis was determined by the follow-up, univariate analysis and multivariate analysis.
RESULTS: We observed decreased miR-181a levels and increased GATA6 expression in LSCC samples compared with control mucosa tissues. Transfection of miR-181a decreased GATA6 expression, suppressed migration and promoted apoptosis in Hep-2 cells. Furthermore, silencing GATA6 suppressed cell migration and promoted apoptosis in Hep-2 cells. Notably, patients with high miR-181a levels had a longer life span.
CONCLUSION: MiR-181a inhibits LSCC progression via suppressing GATA6 expression. MiR-181a is an independent prognostic factor in LSCC patients.

Related:

Apoptosis

Cancer of the Larynx

Warejko JK, Schueler M, Vivante A, et al.
Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.
Hypertension. 2018; 71(4):691-699 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (

Related:

Neurofibromatosis

USA

Seino T, Kawasaki S, Shimokawa M, et al.
Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.
Cell Stem Cell. 2018; 22(3):454-467.e6 [PubMed] Related Publications

Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin. Transcriptome analysis of PDAC organoids revealed gene-expression signatures that associated Wnt niche subtypes with GATA6-dependent gene expression subtypes, which were functionally supported by genetic perturbation of GATA6. Furthermore, CRISPR-Cas9-based genome editing of PDAC driver genes (KRAS, CDKN2A, SMAD4, and TP53) demonstrated non-genetic acquisition of Wnt niche independence during pancreas tumorigenesis. Collectively, our results reveal functional heterogeneity of Wnt niche independency in PDAC that is non-genetically formed through tumor progression.

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Guoping M, Ran L, Yanru Q
miR-143 Inhibits Cell Proliferation of Gastric Cancer Cells Through Targeting GATA6.
Oncol Res. 2018; 26(7):1023-1029 [PubMed] Related Publications

Recent studies have suggested that the dysregulation of microRNAs (miRNAs) plays a critical role in the progression of human cancers, including gastric cancer (GC). miR-143 had been reported to function as a tumor suppressor in GC. However, the exact molecular mechanism of how miR-143 participates in GC progression remains to be determined. In this present study, we revealed that the expression of miR-143 was significantly downregulated in human GC tissues and cell lines compared with normal tissues and a normal gastric epithelium cell line. In addition, upregulation of the expression of miR-143 in a GC cell line inhibited cell proliferation and induced cell cycle arrested in the G0/G1 phase. Furthermore, GATA6 was identified as a direct target of miR-143 in GC using the luciferase reporter assay. Upregulation of miR-143 inhibited the expression of GATA6 in GC cell lines. Moreover, the overexpression of GATA6 could attenuate the effect of miR-143 on cell proliferation in the GC cell lines. Collectively, these data indicated that miR-143 plays a tumor suppressor role partly through regulating the expression of GATA6 in GC. Therefore, targeting miR-143 may be a novel therapeutic method for GC.

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Vinck WJ, Van de Mierop F, Van Mieghem F, et al.
Pancreatic hemi-agenesis in MEN1: A clinical report.
Eur J Med Genet. 2018; 61(4):181-184 [PubMed] Related Publications

We first describe a patient with multiple endocrine neoplasia type 1 (MEN1) and dorsal pancreatic hemi-agenesis. Previously, pancreas divisum has been reported in MEN1. Recent data in mice have elucidated the molecular mechanisms of pancreatic endoderm specification. Disinhibition of hedgehog signaling appears to be important in how Gata4 and Gata6 variants cause pancreatic agenesis. Disinhibition of hedgehog signaling has also been observed in Men1 knockout pancreatic islets. Although we cannot exclude a spurious association between dorsal pancreatic hemi-agenesis and MEN1 in our patient, we argue that developmental abnormalities of the pancreas may have to be considered as possibly related to the MEN1 phenotype.

Related:

MEN1

Song SH, Jeon MS, Nam JW, et al.
Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer.
Oncogene. 2018; 37(8):993-1004 [PubMed] Related Publications

Six GATA transcription factors play important roles in eukaryotic development. Among these, GATA2, an essential factor for the hematopoietic cell lineage, exhibits low expression in human gastric tissues, whereas GATA6, which is crucial for gastrointestinal development and differentiation, is frequently amplified and/or overexpressed in human gastric cancer. Interestingly, we found that GATA6 was overexpressed in human gastric cancer cells only when GATA2 expression was completely absent, thereby showing an inverse correlation between GATA2 and GATA6. In gastric cancer cells that express high GATA6 levels, a GATA2 CpG island is hypermethylated, repressing expression in these cells. In contrast, GATA6 expression is undetectable in GATA2-overexpressing gastric cancer cells, which lack GATA2 DNA methylation. Furthermore, PRC2 complex-mediated transcriptional silencing of GATA6 was observed in the GATA2-overexpressing cells. We also show that the GATA2 and PRC2 complexes are enriched within the GATA6 locus, and that the recruitment of the PRC2 complex is impaired by disrupting GATA2 expression, resulting in GATA6 upregulation. In addition, ectopic GATA2 expression significantly downregulates GATA6 expression, suggesting GATA2 directly represses GATA6. Furthermore, GATA6 downregulation showed antitumor activity by inducing growth arrest. Finally, we show that aberrant GATA2 methylation occurs early during the multistep process of gastric carcinogenesis regardless of Helicobacter pylori infection. Taken together, GATA2 dysregulation by epigenetic modification is associated with unfavorable phenotypes in human gastric cancer cells by allowing GATA6 expression.

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Nikitina AS, Sharova EI, Danilenko SA, et al.
Novel RNA biomarkers of prostate cancer revealed by RNA-seq analysis of formalin-fixed samples obtained from Russian patients.
Oncotarget. 2017; 8(20):32990-33001 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

Due to heterogeneous multifocal nature of prostate cancer (PCa), there is currently a lack of biomarkers that stably distinguish it from benign prostatic hyperplasia (BPH), predict clinical outcome and guide the choice of optimal treatment. In this study RNA-seq analysis was applied to formalin-fixed paraffin-embedded (FFPE) tumor and matched normal tissue samples collected from Russian patients with PCa and BPH. We identified 3384 genes differentially expressed (DE) (FDR < 0.05) between tumor tissue of PCa patients and adjacent normal tissue as well as both tissue types from BPH patients. Overexpression of four of the discovered genes (ANKRD34B, NEK5, KCNG3, and PTPRT) was validated by RT-qPCR. Furthermore, the enrichment analysis of overrepresented microRNA and transcription factor (TF) recognition sites within DE genes revealed common regulatory elements of which 13 microRNAs and 53 TFs were thus linked to PCa for the first time. Moreover, 8 of these TFs (FOXJ2, GATA6, NFE2L1, NFIL3, PRRX2, TEF, EBF2 and ZBTB18) were found to be differentially expressed in this study making them not only candidate biomarkers of prostate cancer but also potential therapeutic targets.

Related:

Prostate Cancer

Tian F, Chen J, Zheng S, et al.
miR-124 targets GATA6 to suppress cholangiocarcinoma cell invasion and metastasis.
BMC Cancer. 2017; 17(1):175 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

BACKGROUND: Our previous study showed that GATA6 plays important roles in cholangiocarcinoma (CCA) cell invasion and metastasis. However, the regulation mechanism of GATA6 in CCA is not clear. In this study, we studied the potential function of miR-124 in CCA and the mechanism of GATA6 regulation.
METHODS: The expression levels of miR-124 and GATA6 in cancerous tissues from 57 CCA patients was detected by RT-PCR and IHC. The impact of miR-124 on GATA6 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay.
RESULTS: miR-124 was decreased in 57 cancerous tissue samples compared with 38 matched paracancerous samples. The miR-124 level was inversely associated with lymph node involvement and distant metastasis. miR-124 significantly inhibited invasion and migration of CCA cells in vitro. Furthermore, miR-124 inhibited CCA cell metastasis in nude mice. miR-124 inhibited the luciferase activity of reporter genes containing the wild-type GATA6 3'-UTR, which was abrogated by mutation of the binding site. The protein levels of GATA6 were negatively regulated by miR-124. miR-124 expression was inversely associated with GATA6 in 57 cancerous samples. The miR-124-induced suppression of CCA invasion was abrogated by remedial expression of GATA6. GATA6 expression was decreased by miR-124 overexpression in liver masses from nude mice.
CONCLUSIONS: Our data suggested that miR-124 decreases GATA6 expression by targeting its 3'-UTR, which in turn inhibits CCA invasion and metastasis.

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Zhang D, Wu X, Liu X, et al.
Piwil2-transfected human fibroblasts are cancer stem cell-like and genetically unstable.
Oncotarget. 2017; 8(7):12259-12271 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

Uncontrolled cell proliferation and inhibition of apoptosis are considered to be vital for cancer initiation, maintenance, infiltration, metastasis and recurrence after anti-cancer therapy. Here we report the generation of a novel cell line by reprogramming child foreskin fibroblast with the full length apoptosis inhibitor gene PIWIL2. The fibroblasts transfected with PIWIL2 expressed the stem cell markers OCT-4, NANOG, SOX-2, KLF-4 and C-MYC; endoderm marker AFP and GATA6; mesoderm markers ACTA2 and BRACHYURY; and ectoderm markers NESTIN and TUBB3. The karyotype was found to be hyperdiploid. The PIWIL2 transfected fibroblast cells grew into tumorous masses within 5 weeks of subcutaneous injection into adult nude mice. Although the injected cell expressed markers for all three germlines, ectoderm, mesoderm, and endoderm, they did not form teratomas in vivo. This study indicates that the PIWIL2 gene could play a key role in cancer induction and maintenance. This method for generating induced tumorigenic cells (ITGC) provides a new research tool to study oncogenesis that in turn may lead to a better understanding of cancer etiology and the development of novel anti-cancer therapies.

Related:

MYC

Peng D, Guo Y, Chen H, et al.
Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas.
Sci Rep. 2017; 7:40729 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. In this study, we carried out an integrative molecular analysis to identify interactions between genomic and epigenomic alterations in regulating gene expression networks in EAC. We detected significant alterations in DNA copy numbers (CN), gene expression levels, and DNA methylation profiles. The integrative analysis demonstrated that altered expression of 1,755 genes was associated with changes in CN or methylation. We found that expression alterations in 84 genes were associated with changes in both CN and methylation. These data suggest a strong interaction between genetic and epigenetic events to modulate gene expression in EAC. Of note, bioinformatics analysis detected a prominent K-RAS signature and predicted activation of several important transcription factor networks, including β-catenin, MYB, TWIST1, SOX7, GATA3 and GATA6. Notably, we detected hypomethylation and overexpression of several pro-inflammatory genes such as COX2, IL8 and IL23R, suggesting an important role of epigenetic regulation of these genes in the inflammatory cascade associated with EAC. In summary, this integrative analysis demonstrates a complex interaction between genetic and epigenetic mechanisms providing several novel insights for our understanding of molecular events in EAC.

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CGH

Cancer of the Esophagus

Esophageal Cancer

Fantini S, Salsi V, Reggiani L, et al.
The miR-196b miRNA inhibits the GATA6 intestinal transcription factor and is upregulated in colon cancer patients.
Oncotarget. 2017; 8(3):4747-4759 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

OBJECTIVE: To explore the possible misexpression of the microRNA miR-196b in colorectal cancer (CRC) and its role in controlling the expression of GATA6, a putative target gene crucial to intestinal cell homeostasis and tumorigenesis.
DESIGN: The expression of miR-196b was analysed by qRT-PCR in surgical resection samples from a cohort of sporadic colon cancer patients. Manipulations of miR-196b expression were performed to demonstrate its inhibition of GATA6 protein levels.
RESULTS: We found that miR-196b is significantly upregulated in pre-treatment surgical resection samples from a cohort of sporadic colon cancer patients. The upregulation of miR-196b correlates with less severe clinicopathological characteristics, such as early tumor stage and absence of lymph node metastases. We show that in CRC cells, miR-196b targets the mRNA of GATA6, a transcription factor involved in the homeostasis and differentiation of intestinal epithelial cells, and a positive regulator of the Wnt/β-catenin pathway. We moreover found that the increase of miR-196b correlates with a reduced GATA6 protein expression in colon cancer patients.
CONCLUSION: Our results establish miR-196b as a post-transcriptional inhibitor of GATA6 in CRC cells, implicating miR-196b function in gene regulatory pathways crucial to intestinal cell homeostasis and tumorigenesis. Our results furthermore suggest a role of miR-196b expression in CRC, as an antagonist of GATA6 function in tumor cells, thus providing the basis for a potential targeting strategy for the treatment of CRC.

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Kondratyeva LG, Sveshnikova AA, Grankina EV, et al.
Downregulation of expression of mater genes SOX9, FOXA2, and GATA4 in pancreatic cancer cells stimulated with TGFβ1 epithelial-mesenchymal transition.
Dokl Biochem Biophys. 2016; 469(1):257-9 [PubMed] Related Publications

We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFβ1. Our results indicate the absence of induction of expression of PTF1A, PDX1, HNF1b, NEUROG3, RPBJL, NKX6.1, and ONECUT1 genes, which are inactive in PANC1 cell line after the EMT stimulated by TGFβ1.

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TGFB1

CDH1

Wu CS, Wei KL, Chou JL, et al.
Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer.
Int J Mol Sci. 2016; 17(9) [PubMed] Article available free on PMC after 13/12/2019 Related Publications

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.

Related:

TFF1

Duggan SP, Behan FM, Kirca M, et al.
The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival.
Sci Rep. 2016; 6:32638 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

Barrett's oesophagus (BO), an intestinal-type metaplasia (IM), typically arising in conjunction with gastro-oesophageal reflux disease, is a prominent risk factor for the development of oesophageal adenocarcinoma (OAC). The molecular similarities between IM and normal intestinal tissues are ill-defined. Consequently, the contribution of intestine-enriched factors expressed within BO to oncogenesis is unclear. Herein, using transcriptomics we define the intestine-enriched genes expressed in meta-profiles of BO and OAC. Interestingly, 77% of the genes differentially expressed in a meta-profile of BO were similarly expressed in intestinal tissues. Furthermore, 85% of this intestine-like signature was maintained upon transition to OAC. Gene networking analysis of transcription factors within this signature revealed a network centred upon NR5A2, GATA6 and FOXA2, whose over-expression was determined in a cohort of BO and OAC patients. Simulated acid reflux was observed to induce the expression of both NR5A2 and GATA6. Using siRNA-mediated silencing and an NR5A2 antagonist we demonstrate that NR5A2-mediated cancer cell survival is facilitated through augmentation of GATA6 and anti-apoptotic factor BCL-XL levels. Abrogation of NR5A2-GATA6 expression in conjunction with BCL-XL co-silencing resulted in synergistically increased sensitivity to chemotherapeutics and photo-dynamic therapeutics. These findings characterize the intestine-like signature associated with IM which may have important consequences to adenocarcinogenesis.

Related:

Apoptosis

Cancer of the Esophagus

Esophageal Cancer

NR5A2

Hu H, Sun Z, Li Y, et al.
The Histologic Classifications of Lung Adenocarcinomas Are Discriminable by Unique Lineage Backgrounds.
J Thorac Oncol. 2016; 11(12):2161-2172 [PubMed] Related Publications

OBJECTIVES: Lung adenocarcinomas are a heterogeneous set of diseases with distinct genetic and histologic characteristics. Besides the discovery of oncogenic mutations and introduction of the histologic classifications (2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society and 2015 WHO), increasing evidence has linked this intertumor heterogeneity to the lung lineage-specific pathways and lineage genes. Therefore, in this study, we assessed the gene expression of identified lung lineage genes to study their role in distinguishing lung adenocarcinoma diversities.
METHODS: A total of 278 surgically resected lung adenocarcinomas were included. Each case was evaluated for genetic mutations and histologic classification. Lineage genes associated with respiratory tract differentiation (NK2 homeobox 1 gene [NKX2-1], GATA protein binding 6 gene [GATA6], foxhead box J1 gene [FOXJ1], and SAM pointed domain containing ETS transcription factor gene [SPDEF]) and stem/basal-like status (inhibitor of DNA binding 2, HLH protein gene [ID2], POU class 5 homeobox 1 gene [POU5F1], SRY-box 2 gene [SOX2], and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC]) were selected. mRNA expression of these genes in each tumor sample was assessed by quantitative real-time polymerase chain reaction and normalized to paired normal lung tissue.
RESULTS: Distinct lineage gene expressions were found on the basis of genetic and histologic diversities. Expression of NKX2-1, GATA6, FOXJ1, and POU5F1 exhibited a significant linear relationship across histologic subgroups that was independent of genetic mutation status. Expression levels of NKX2-1 and POU5F1 were also associated with EGFR mutation status, independent of histologic subtypes. Further analysis revealed that the overexpression of SPDEF defined longer relapse-free survivals, especially in stage I disease.
CONCLUSIONS: For the first time, we showed the unique lineage backgrounds of different histologic subtypes and oncogenic mutations. Assessing this added parameter might be beneficial in discriminating intertumor heterogeneity, advancing target exploration, developing theranostic/prognostic biomarkers, and designing clinical trials.

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Lung Cancer

Martinelli P, Carrillo-de Santa Pau E, Cox T, et al.
GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer.
Gut. 2017; 66(9):1665-1676 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

BACKGROUND AND AIMS: The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC.
DESIGN: We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy.
RESULTS: GATA6 inhibits the epithelial-mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET
CONCLUSIONS: We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.

Related:

Fluorouracil

Adrenocortical Carcinoma - Molecular Biology

Kubota-Nakayama F, Nakamura Y, Konosu-Fukaya S, et al.
Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies.
Hum Pathol. 2016; 54:165-73 [PubMed] Related Publications

Adrenal Cushing syndrome (CS) is caused by the overproduction of cortisol in adrenocortical tumors including adrenal cortisol-producing adenoma (CPA). In CS, steroidogenic enzymes such as 17α-hydroxylase/17, 20-lase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B), and 11β-hydroxylase (CYP11B1) are abundantly expressed in tumor cells. In addition, several transcriptional factors have been reported to play pivotal roles in the regulation of these enzymes in CPA, but their correlations with those enzymes above have still remained largely unknown. Therefore, in this study, we examined the status of steroidogenic enzymes and their transcriptional factors in 78 and 15 CPA cases by using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), respectively. Immunoreactivity of HSD3B2, CYP11B1, CYP17A1, steroidogenic factor-1 (SF1[NR5A1]), GATA6, and nerve growth factor induced-B (NGFIB[NR4A1]) was detected in tumor cells. Results of qPCR analysis revealed that expression of HSD3B2 mRNA was significantly higher than that of HSD3B1, and CYP11B1 mRNA was significantly higher than CYP11B2. In addition, the expression of CYP11B1 mRNA was positively correlated with those of NR5A1, GATA6, and NR4A1. These results all indicated that HSD3B2 but not HSD3B1 was mainly involved in cortisol overproduction in CPA. In addition, NR5A1, GATA6, and NR4A1 were all considered to play important roles in cortisol overproduction through regulating CYP11B1 gene transcription.

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Adrenocortical Cancer

NR4A1

CYP17A1

Murphy SJ, Hart SN, Halling GC, et al.
Integrated Genomic Analysis of Pancreatic Ductal Adenocarcinomas Reveals Genomic Rearrangement Events as Significant Drivers of Disease.
Cancer Res. 2016; 76(3):749-61 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

Many somatic mutations have been detected in pancreatic ductal adenocarcinoma (PDAC), leading to the identification of some key drivers of disease progression, but the involvement of large genomic rearrangements has often been overlooked. In this study, we performed mate pair sequencing (MPseq) on genomic DNA from 24 PDAC tumors, including 15 laser-captured microdissected PDAC and 9 patient-derived xenografts, to identify genome-wide rearrangements. Large genomic rearrangements with intragenic breakpoints altering key regulatory genes involved in PDAC progression were detected in all tumors. SMAD4, ZNF521, and FHIT were among the most frequently hit genes. Conversely, commonly reported genes with copy number gains, including MYC and GATA6, were frequently observed in the absence of direct intragenic breakpoints, suggesting a requirement for sustaining oncogenic function during PDAC progression. Integration of data from MPseq, exome sequencing, and transcriptome analysis of primary PDAC cases identified limited overlap in genes affected by both rearrangements and point mutations. However, significant overlap was observed in major PDAC-associated signaling pathways, with all PDAC exhibiting reduced SMAD4 expression, reduced SMAD-dependent TGFβ signaling, and increased WNT and Hedgehog signaling. The frequent loss of SMAD4 and FHIT due to genomic rearrangements strongly implicates these genes as key drivers of PDAC, thus highlighting the strengths of an integrated genomic and transcriptomic approach for identifying mechanisms underlying disease initiation and progression.

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Non-Small Cell Lung Cancer

Signal Transduction

Antontseva EV, Matveeva MY, Bondar NP, et al.
Regulatory single nucleotide polymorphisms at the beginning of intron 2 of the human KRAS gene.
J Biosci. 2015; 40(5):873-83 [PubMed] Related Publications

There are two regulatory single nucleotide polymorphisms (rSNPs) at the beginning of the second intron of the mouse K-ras gene that are strongly associated with lung cancer susceptibility. We performed functional analysis of three SNPs (rs12228277: T greater than A, rs12226937: G greater than A, and rs61761074: T greater than G) located in the same region of human KRAS. We found that rs12228277 and rs61761074 result in differential binding patterns of lung nuclear proteins to oligonucleotide probes corresponding two alternative alleles; in both cases, the transcription factor NF-Y is involved. G greater than A substitution (rs12226937) had no effect on the binding of lung nuclear proteins. However, all the nucleotide substitutions under study showed functional effects in a luciferase reporter assay. Among them, rs61761074 demonstrated a significant correlation with allele frequency in non-small-cell lung cancer (NSCLC). Taken together, the results of our study suggest that a T greater than G substitution at nucleotide position 615 in the second intron of the KRAS gene (rs61761074) may represent a promising genetic marker of NSCLC.

Related:

Lung Cancer

Song Y, Tian T, Fu X, et al.
GATA6 is overexpressed in breast cancer and promotes breast cancer cell epithelial-mesenchymal transition by upregulating slug expression.
Exp Mol Pathol. 2015; 99(3):617-27 [PubMed] Related Publications

Metastasis is the leading cause of death in breast cancer (BC) patients. However, until now, the mechanisms of BC metastasis remain elusive. GATA6 is a member of the GATA transcription factor family that plays critical regulatory roles in tissue development, which has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in BC remain unclear. Here we show that GATA6 is elevated in BC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of GATA6 was associated with decreased overall survival of BC patients. Overexpression of GATA6 in BC cells increased epithelial-mesenchymal transition. In contrast, silencing GATA6 in aggressive BC cells inhibited this process. Mechanistically, we found GATA6 exerts its function through active slug transcription. Slug knockdown blocked the GATA6-driven EMT. Furthermore, slug expression in human BC is positively correlated with GATA6 expression. Our results, for the first time, portray a pivotal role of GATA6 in regulating metastatic behaviors of BC cells, suggesting GATA6 is a potential therapeutic target in metastatic BCs.

Related:

Breast Cancer

Kim JS, Kurie JM, Ahn YH
BMP4 depletion by miR-200 inhibits tumorigenesis and metastasis of lung adenocarcinoma cells.
Mol Cancer. 2015; 14:173 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

BACKGROUND: MicroRNA-200 (miR-200) suppresses the epithelial-mesenchymal transition of various cancer cells, including lung adenocarcinoma cells. We found that bone morphogenetic protein 4 (BMP4) was decreased in miR-200-overexpressing cells and epithelial-like lung cancer cells. In this study, we investigated the mechanism and role of BMP4 depletion by miR-200 in murine lung adenocarcinoma cells.
METHODS: BMP4 expression levels in murine lung cancer cells were measured by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Promoter and 3'-untranslated region (UTR) luciferase reporter assays were performed to discover the mechanism of regulation of BMP4 by miR-200. Murine lung cancer cells were transfected with Bmp4 shRNAs, which were then injected into syngeneic mice to measure their tumorigenic and metastatic potential and cultured on Matrigel to study the influence of BMP4 on 3-D acinus formation.
RESULTS: miR-200 down-regulated BMP4 via direct targeting of the GATA4 and GATA6 transcription factors that stimulate Bmp4 transcription. BMP4 up-regulated JAG2, an upstream factor of miR-200; therefore, JAG2, miR-200, and BMP4 form a regulatory loop. Bmp4 knockdown suppressed cancer cell growth, migration, and invasion and inhibited tumorigenesis and metastasis of lung cancer cells when injected into syngeneic mice. In addition, BMP4 was required for normal acinus formation in Matrigel 3-D culture of murine lung cancer cells, which may be mediated by MYH10, a downstream target of BMP4.
CONCLUSION: BMP4 functions as a pro-tumorigenic factor in a murine lung cancer model, and its transcription is regulated by miR-200 and GATA4/6. Thus, we propose that BMP4 and its antagonists may be suitable therapeutic targets for the treatment of lung cancer.

Related:

Lung Cancer

Kawasaki Y, Matsumura K, Miyamoto M, et al.
REG4 is a transcriptional target of GATA6 and is essential for colorectal tumorigenesis.
Sci Rep. 2015; 5:14291 [PubMed] Article available free on PMC after 13/12/2019 Related Publications

The transcription factor GATA6 is a critical regulator of cell proliferation and development in the gastrointestinal tract. We have recently reported that GATA6 induces the expression of the intestinal stem cell marker LGR5 and enhances the clonogenicity and tumorigenicity of colon cancer cells, but not the growth of these cells cultured under adherent conditions. Here we show that REG4, a member of the regenerating islet-derived (REG) family, is also a target of GATA6. We further demonstrate that REG4 is downregulated by overexpression of miR-363, which suppresses GATA6 expression. Moreover, we show that GATA6-mediated activation of REG4 enhances the growth of colon cancer cells under adherent conditions and is required for their tumorigenicity. Taken together, our findings demonstrate that GATA6 simultaneously induces the expression of genes essential for the growth of colon cancer cells under adherent conditions (REG4) and genes required for their clonogenicity (LGR5), and that the miR-363-GATA6-REG4/LGR5 signaling cascade promotes the tumorigenicity of colon cancer cells.

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